Structure and dynamics of meiotic chromosomes

减数分裂染色体的结构和动力学

基本信息

批准号：
10455454
负责人：
Ofer Rog
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

Chromosome segregation during meiosis places one chromosome, either the maternal or paternal copy, in each gamete. Accurate segregation of genetic material requires that the parental chromosomes interact with one another and exchange genetic information through the formation of crossovers. Crossover formation requires that chromosomes undergo an orchestrated series of morphological transformations. Failure to make crossovers leads to errors in meiotic chromosome segregation, and consequently to infertility and congenital birth defects. The research proposed here will use nematodes and budding yeast to address the mechanisms of chromosome interaction and segregation by employing experimental approaches that take advantage of the unique features of these model systems, including direct imaging of chromosome dynamics in living animals. The molecular mechanisms that allow chromosomes to form, regulate, and respond to crossovers are poorly understood. This proposal probes three aspects of meiotic chromosome organization and dynamics. The first project will explore how the Synaptonemal Complex (SC)—a conserved structure that assembles between homologous chromosomes and regulates the distribution of crossovers—implements chromosome-wide regulation. This work builds on the recent understanding that the SC, despite its ordered appearance when visualized by electron microscopy, is a liquid-like phase-separated compartment. A novel mutagenesis and genetic screening strategy will isolate separation-of-function mutations that perturb the liquid properties of the SC, and in that way assign specific functions to SC components. In addition, poorly understood chromosome- wide SC dynamics will be directly visualized for the first time using long-term live-imaging. A mechanistic understanding of these dynamics will explain how the meiotic program responds to karyotype abnormalities, and how the SC regulates, and responds to, crossovers. The second project focuses on the reorganization of the chromosomes that transforms crossovers—a local exchange of DNA strands—into the connections that hold the parental chromosomes together during the meiotic divisions, and promotes their correct segregation into gametes. A novel way to label only one of the two parental chromosomes and to visualize its morphology throughout meiosis will rely on the advantageous organization of chromosomes in the C. elegans gonad and on super-resolution microscopy. The third project addresses the organization of meiotic chromosomes as loops of chromatin that are anchored at their base to a proteinaceous axis. This conserved chromosome organization is integral to the meiotic program, but the mechanisms regulating its assembly and dynamics remain enigmatic. A novel technique to obtain a high-resolution description of chromosome conformation and dynamics in budding yeast will take advantage of an emerging technology to sequence very long molecules of DNA. This technique could be widely applied to probe chromosome organization in other cellular processes.

减数分裂过程中的染色体分离将一条染色体（母本或父本）置于每个配子的遗传物质的准确分离需要亲本染色体相互作用。彼此之间并通过交叉形成交换遗传信息。要求染色体经历一系列精心策划的形态转变。交叉导致减数分裂染色体分离错误，从而导致不孕和先天性畸形这里提出的研究将使用线虫和芽殖酵母来解决这一机制。通过采用利用优势的实验方法来研究染色体相互作用和分离这些模型系统的独特功能，包括活体动物染色体动态的直接成像。允许染色体形成、调节和响应交叉的分子机制尚不清楚该提案探讨了减数分裂染色体组织和动力学的三个方面。该项目将探索联会复合体（SC）——一种保守的结构，在同源染色体并调节交叉的分布——实现染色体范围这项工作建立在最近的理解之上，即 SC 尽管其有序出现。通过电子显微镜观察，它是一种类似液体的相分离隔室。遗传筛选策略将分离出扰乱液体特性的功能分离突变 SC，并以这种方式将特定功能分配给 SC 组件此外，人们对染色体知之甚少。首次使用长期实时成像机制直接可视化宽 SC 动态。了解这些动态将解释减数分裂程序如何响应核型异常，以及 SC 如何监管和应对交叉。第二个项目重点关注改变交叉的染色体重组——局部交叉 DNA 链的交换——在发育过程中将亲本染色体固定在一起的连接减数分裂，并促进它们正确分离成配子，这是一种仅标记其中一个的新颖方法。两条亲代染色体并在整个减数分裂期间可视化其形态将依赖于有利的线虫性腺中染色体的组织和超分辨率显微镜。第三个项目将减数分裂染色体组织为锚定的染色质环这种保守的染色体组织是减数分裂的组成部分。程序，但调节其组装和动力学的机制仍然是一种神秘的技术。获得芽殖酵母染色体构象和动力学的高分辨率描述将需要这项技术的优势在于可以对很长的 DNA 分子进行测序。广泛应用于探测其他细胞过程中的染色体组织。